Anti-cancer agents have various types such as an alkylating agent, a platinum agent, an antimetabolite, an antitumor antibiotic, and an antitumor plant alkaloid. These anti-cancer agents are effective for some cancers but not effective for other cancers. Even when an anti-cancer agent is confirmed to be effective for a certain cancer, the anti-cancer agent is effective for some patients and not effective for other patients, leading to interindividual differences. Whether or not a cancer of a specific patient has response to an anti-cancer agent is designated as sensitivity to the anti-cancer agent.
Oxaliplatin, (SP-4-2)-[(1R,2R)-cyclohexane-1,2-diamine-κN,κN′][ethanedioato(2-)-κO1,κO2]platinum (IUPAC), is a third-generation platinum-based complex anti-cancer agent. Similar to precedent drugs (cisplatin (CDDP) and carboplatin (CBDCA)), the action mechanism thereof is thought to be based on inhibition of DNA synthesis and/or protein synthesis via cross-linking with DNA bases. Oxaliplatin (L-OHP) exhibits anti-tumor effect on colorectal cancer, to which CDDP or CBDCA is ineffective, and shows different spectrum of anti-tumor activity from that of a precedent platinum-based complex anti-cancer agent. In the United States of America, oxaliplatin for use in combination with fluorouracil (5-FU) and levofolinate (LV) was approved as a first line therapy for metastatic colorectal cancer in January, 2004. In Japan, oxaliplatin was listed in the National Health Insurance (NHI) price list in the case of combination use thereof with continuous infusional fluorouracil and levofolinate (FOLFOX4 regimen) for “advanced/recurrent colorectal cancer not amenable to curative surgical resection” in April, 2005. Until the early 1990's, 5-FU/LV regimen to advanced/recurrent colorectal cancer has provided a survival of 10 to 12 months. In contrast, a FOLFOX regimen combined with oxaliplatin results in a prolonged survival of 19.5 months (about twice the survival time). In August, 2009, an indication of oxaliplatin combined with continuous infusional fluorouracil and levofolinate to “postoperative adjuvant chemotherapy for colon cancer” was added to efficacy and effectiveness. Thus, oxaliplatin is a promising drug having an efficacy in an increased number of colorectal cancer patients.
However, the response rate of FOLFOX regimen against advanced/recurrent colorectal cancer is still as low as about 50%. In other words, about half of the treated patients achieve no effects. During administration of oxaliplatin, peripheral neuropathy frequently occurs in addition to neutropenia. Although not being fatal, these adverse events are factors which make continuation of the therapy difficult. Therefore, if there is a biomarker which can predict, before start of the treatment, a patient who is expected to achieve the response (i.e., a responder) and a patient who is not expected to achieve the response (i.e., a non-responder), to thereby diagnose the therapeutic response earlier, a chemotherapy ensuring high effectiveness and high safety can be established.
There have been a number of reports on sensitivity/resistance factor with respect to platinum-based chemotherapy, but most of them are focused on cisplatin. The therapeutic response of patients to oxaliplatin, which is structurally and functionally similar to cisplatin, is thought to generally relate to, for example, the following:
1) enhancement of the ability of excising and repairing DNA damaged by oxaliplatin;
2) inactivation (detoxification) of oxaliplatin (active form) in cells; and
3) reduction in accumulation amount of oxaliplatin in cells. In the oxaliplatin+5-FU combination therapy for colorectal cancer patients, the therapeutic response and prognosis-predicting factor are now under study on the basis of 1) to 3).
Regarding 1), the excision repair cross-complementing group 1 (ERCC1) gene expression level in tumor cells is reported to serve as a prognosis factor, the ERCC1 playing an important role in nucleotide excision repair (NER) (Non-Patent Document 1). Patients having a C/C homozygote of C118T (a type of single nucleotide polymorphism (SNP) of ERCC1) exhibit a survival longer than that of patients having at least one T allele (Non-Patent Document 2). In Xeroderma pigmentosum D (XPD, also known as ERCC2), a genetic polymorphism involving Lys751Gln amino acid mutation is reported to relate to percent tumor reduction and survival (Non-Patent Documents 2 and 3). In base excision repair (BER), there has been reported a relationship between the tumor reduction effect and a genetic polymorphism involving Arg399Gln amino acid mutation in X-ray repair cross-complementing group 1 (XRCC1) encoding a protein relating to effective repair of DNA single strand breakage caused by exposure to an alkylating agent or the like (Non-Patent Document 4). However, further analysis of the same patients has revealed that the genetic polymorphism does not affect the clinical prognosis (Non-Patent Document 2). DNA mismatch repair (MMR) is thought to relate to lowering sensitivity to cisplatin. However, in vitro studies have revealed that MMR does not involve repair of DNA damaged by oxaliplatin (Non-Patent Document 5).
Regarding 2), glutathione-S-transferase (GST) is an enzyme which catalyzes phase II reaction in the detoxification and metabolism. GST catalyzes formation of a conjugation of a DNA-platinum adduct and glutathione, to thereby inactivate a drug. Among GST subtypes, GSTP1 has a high expression level in colorectal cancer, and a genetic polymorphism involving Ile105Val amino acid mutation relates to survival (median survival: Ile/Ile 7.9 months, Ile/Val 13.3 months, Val/Val 24.9 months) (Non-Patent Document 6).
Regarding 3), studies employing cultured cells have revealed that organic cation transporters (OCTs) relate to transportation of oxaliplatin into cells and sensitivity to oxaliplatin (Non-Patent Document 7). A relationship between copper- and heavy-metal-transporters such as ATP7A and ATP7B and sensitivity has also been reported (Non-Patent Documents 8 and 9). However, the relationship between expression of these transporters and therapeutic response to oxaliplatin has not been clinically elucidated.
Recent clinical studies for advanced colorectal cancer patients having received FOLFOX regimen have revealed that a genetic polymorphism of ERCC1 (Asn118Asn) and that of XPD (Lys751Gln) independently relate to progression-free survival (PFS), and that a genetic polymorphism of GSTP1 (Ile105Val) does not relate to PFS but tends to have a relationship with oxaliplatin-induced neurotoxicity (Non-Patent Document 10).
In vitro studies have revealed a number of resistance-related factors of cisplatin (a precedent platinum-based complex drug), and the relationship between oxaliplatin and apoptosis-related factors such as FAS/FASL and Bcl-xL have been reported (Non-Patent Documents 11 and 12). However, oxaliplatin exhibits a therapeutic response differing from that of cisplatin, depending on the type of cancer. In addition, there has not been substantially elucidated the cell response of cancer cells with respect to a platinum-DNA adduct, which exerts cytotoxic activity of oxaliplatin. Thus, there has been established no definite biomarker which can predict the therapeutic response to chemotherapy employing oxaliplatin.
Meanwhile, fluorouracil is a fluoro-pyrimidine anti-cancer agent developed in 1957 and even now serves as a basic drug for use in the chemotherapy of gastrointestinal cancer. When incorporated into cancer cells, fluorouracil exerts cytotoxic effect through a principle action mechanism of DNA synthesis inhibition induced by inhibition of thymidylate synthase (TS) by an active metabolite, fluorodeoxyuridine-5′-monophosphate (FdUMP), and another mechanism of RNA function inhibition by an active metabolite, 5-fluorouridine triphosphate (FUTP).
Hitherto, many studies have been conducted to predict therapeutic response to fluoro-pyrimidine anti-cancer agents. In particular, many studies have been focused on dihydropyrimidine dehydrogenase (DPD), which is a fluorouracil degrading enzyme, and thymidylate synthase (TS), which is a target enzyme of an active metabolite. A tumor in which DPD, a rate-limiting enzyme in the catabolism of fluorouracil, is highly expressed is reported to have resistance to fluorouracil (Non-Patent Document 13), but a limited number of studies have been conducted with clinical specimens. The TS expression level is reported to be a possible factor that determines the therapeutic effect by a fluoro-pyrimidine anti-cancer agent, even when the expression level is determined through any assay method such as the enzymatic activity method, protein level assay, or RNA level assay (Non-Patent Documents 14 and 15). However, the above-obtained results are not completely the same, and there has been known no definite biomarker which can predict the therapeutic response to fluorouracil in an early treatment stage.
In metastatic colorectal cancer patients having fluorouracil resistance, ERCC1 and TS mRNA expression levels in tumor cells are reported to serve as factors that predict therapeutic response to 5-FU/L-OHP combination therapy (Non-Patent Document 16). However, recently, large-scale prospective clinical trial (FOCUS trial) for investigating biomarkers that predict therapeutic response of advanced colorectal cancer patients to chemotherapy has revealed that ERCC1 does not serve as a significant predictive factor for 5-FU/L-OHP combination therapy, and that only topoisomerase-1 (Topo1) exhibits weak relationship thereto (Non-Patent Document 17). This indicates that there has been established no biomarker that can reliably select a patient who is expected to be effectively treated through the 5-FU/L-OHP combination therapy. Furthermore, since the therapy schedule of cancer chemotherapy generally requires a long period of time, continuous monitoring of sensitivity of a target patient to a target anti-cancer agent during the therapy can determine whether or not the therapy should be continued. Thus, such monitoring is thought to be meritorious from the viewpoints of reduction or mitigation of the burden on patients and adverse events, leading to reduction in medical cost. Therefore, there is keen demand for establishment of a biomarker that can predict the effect of 5-FU, L-OHP, or a combination of 5-FU/L-OHP or that can determine therapeutic response in an early stage, for the purpose of predicting therapeutic response of individual patients and establishing diagnosis in an early stage to select an appropriate drug and treatment regimen; i.e., for realizing “personalized therapy.”